Viewpoint

μ-Opioid receptor agonists are commonly utilized as analgesics for treatment of acute pain and some chronic pain syndromes.
In addition to their outstanding effectiveness, opioids, unfortunately, promote respiratory depression. Indeed, opioid–induced
respiratory depression can result in hypoventilation and neurologic injury, and may arise as a consequence of μ-opioid receptor–mediated
blockade of specialized respiratory neurons in the brainstem. Manzke and coworkers have suggested that the serotonin receptor
subtype 5-HT4a (5-HT4aR) could serve as a useful therapeutic target for the treatment or prevention of opioid–induced respiratory depression. This
hypothesis derives from the finding that the 5-HT4aR and the μ-opioid receptors affect the intracellular concentration of cyclic AMP in opposing ways. The findings are a significant
milestone in ongoing efforts to understand the analgesia–ventilation link.

Reviews

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Miller B. Jones,

David P. Siderovski,

and Shelley B. Hooks

The gβγ Dimer as a Novel Source of Selectivity in G-Protein Signaling: GGL-ing AT CONVENTION

Heterotrimeric Gαβγ proteins regulate the transduction of extracellular signals from a vast number of cell surface receptors.
One mechanism for integrating the diverse molecular messages that are received by G protein–coupled receptors is the production
of multiple isoforms of the three subunits that constitute the G protein. A multiplicity of Gα forms has been recognized for
some time, but it is also becoming clear that the β- and γ-subunits exist in varying forms that, in heterodimeric combinations,
can specify alternative downstream signals as well as interact selectively with particular Gα isoforms. Key to developing
therapeutics that can refine or limit physiological and pathophysiological G protein–propagated signals will be an understanding
of the roles and combinatorial potential of distinct Gα, Gβ, and Gγ species, including their associations with other proteins.

Designing better inhalational anesthetics may be as simple as identifying those volatile compounds that target specific protein
domains, resulting in the disruption of multiprotein complexes at synaptic termini. New research reveals that biologically
useful concentrations of inhaled anesthetics can interrupt the interactions between PDZ domains and their cognate binding
sites (i.e., other PDZ domains and different motifs) on other proteins. Thus, the authors point out, a sophisticated two-pronged
approach to improved anesthesia might involve tailoring some compounds that target synaptic receptor activity and other compounds
that target intracellular PDZ domain–mediated interactions located proximal to the synapse.

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Terry Kenakin

Allosteric Modulators: The New Generation of Receptor Antagonist

The development of new drugs is frequently configured as a search for “blockers” of specific molecular signals (i.e., a search
for simple competitive antagonists). In contrast, allosteric antagonists can be sought for their ability to “permit” receptor
function, albeit described by altered kinetics, with regard to a particular agonist. Indeed, the use of permissive antagonists—or
better said, permissive “modulators,” for they may actually promote agonism—offers therapeutic modalities distinct from simple
“blockers.” An allosteric change that may obliterate receptor function with respect to one agonist, for example, may be inconsequential
with respect to another. An appreciation of this selective aspect of allostery can thus be relevant to any attempt to “block”
receptor function.